It has been reported that Notch signaling is an evolutionarily highly conserved in vertebrate and invertebrate animals and plays a very pivotal role in determining the fate of cells in the initial stage of development. Notch signaling is known as a major pathway that regulates the differentiation of neural cells, intraocular cells, lymphocytes, muscular cells, hematocytes and the like and is also involved in the development of blood vessels. Mammals have four Notch receptors (Notch 1, 2, 3 and 4), and each of Notch receptors is synthesized as a protein having a size of 300-350 kDa and cleaved at the S1 site by furin-like convertase in the Golgi to form a heterodimer on the cell surface. In addition, four Notch ligands (jagged-1/2 and delta-like ligand (DLL) 1/3/4) were found in mammals.
Activated Notch signaling is known to induce tumorigenesis in various tumor models. When the activated Notch NICD was expressed in rat hematopoietic cells, T-cell leukemia/lymphomas occurred, and activated Notch 1 was found in about 50% of T-ALL (T-cell acute lymphoblastic leukemia). In addition, in the case of breast cancer, Notch 4 receptor was found to be overexpressed in rats (Czech II) introduced with MMTV (mouse mammary tumor virus), and the occurrence of a mammary gland tumor in these rats has been reported. It has been reported that Notch receptors and ligands and Notch signaling targets are activated in various cancers such as cervical cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer and prostate cancer. It is known that Notch 1 receptor is associated with worse prognosis on breast cancer patients and associated with the metastasis of prostate cancer.
Delta-like ligand 4 (DLL4) (hereinafter referred to as “DLL4”) is one of delta-class ligands that bind to Notch proteins which are overexpressed in vascular endothelial cells. It is known as a major factor that regulates angiogenesis. DLL4 particularly binds to Notch 1 or Notch 4 receptor which is overexpressed in vascular endothelial cells. It is known that DLL4 is highly overexpressed in cancer blood vessels, although it is also expressed in normal blood vessels. Angiogenesis refers to the mechanism by which new blood vessels are formed from the pre-existing blood vessels. Particularly, in tumors, angiogenesis is caused by angiogenic factors such as VEGF (vascular endothelial growth factor) in order to supply oxygen and nutrients to the hypoxia area of cancer tissue. It is known that angiogenesis in tumors plays an important role not only in the growth of the tumor, but also in the metastasis of the tumor. When Notch signaling by DLL4 in tumors is blocked, angiogenesis cannot be easily controlled, and thus the growth of the tumors can be inhibited. In addition, when Notch signaling by DLL4 is inhibited, autoimmune disease can be treated by increasing the number of regulatory T cells (Treg) (US Patent Publication No. 2011-0189200). For these reasons, DLL4 becomes a new target in the treatment of cancers and autoimmune diseases.
Meanwhile, as an anticancer antibody drug for inhibiting angiogenesis, Avastin® (Genentech/Roche) that targets VEGF was approved by the FDA in 2004 and has been largely successful as an anticancer therapeutic agent. However, recent clinical model and preclinical animal model studies have indicated that all solid tumors do not respond to VEGF inhibitors, and have also reported a number of cases in which some tumors treated with VEGF inhibitors in the initial stage show resistance after a certain time. In addition, study results have been reported which indicate that the administration of VEGF inhibitors converts cancer cells into cancer cells that are more aggressive and easily metastasize. Such study reports have propelled research and development of novel anticancer targets that overcome Avastin resistance or that have efficacy superior to that of Avastin. Among such novel anticancer targets, proteins that are involved in the DLL4/Notch signaling pathway are attracting attention. According to the study results reported to date, it is expected that, because the VEGF/VGEFR signaling pathway and the DLL4/Notch signaling pathway influence angiogenesis by different mechanisms, stronger synergistic anticancer effects can be obtained when the two signaling pathways are all inhibited.